Production of cyclopentanophenan-threne compounds



vniwsw Farm 9 PRODUCTION OFCYCLOPENTANOPHENAN THRENE COMPOUNDS 1 Sondheimer and George Rosenkranz, Mexico City,

Mexico, assignors to Syntex, S.A., Mexico City, Mexico,

a corporation 'of Mexico I No Drawing. Original application July '15, 1954, Serial No. 443,706, now Patent No. 2,827,4 69,,datefd March 18, 1958. Divided and this application Decemberj 'lz, 1957, Serial No. 718,102

Claims priority, application'Mexico July 17, I

7 Claims. (Cl. 260-3914) The present'invention relates to a novel method for the production of cyclopentanophenanthrene compounds.

This application is a division of application Serial'No. 443,706, filed July 15, -1954,- now US. Patent No. 2,827,469, issued March 18, 1958.

More particularly, the present invention relates to a compounds, hydroxy groups and/or esterified hydroxy groups in vicinal position, totheme-unsaturated.keto grouping. The present method is especially applicable to the removal of hydroxy groups and/ or esterified hydroxy groups in position 0-2 and/or position 0-6 of a steroidal A -3-keto compound.

Although steroidal compounds containing the A -3-keto grouping and a hydroxyl group vinical thereto are useful for some purposes, such compounds are produced in many instances as unwanted secondary products; as for example, in the microbiological oxidation of steroids having as a primary aim the production of ll-hydroxy compounds, United States Patent No.'2,602,769. Such by-products are also produced in the oxidation of progesterone to desoxycorticosterone with lead tetracetate wherein there is formed by way of side reaction 2-acetoxy compounds. It is therefore of importance to provide a method for removing from such compounds the 2 and/ or 6-hydroxy groups to thereby produce or recover the original starting material or other valuable compounds.

In accordance with the present invention there has been discovered a process for removing in steroidal compounds, hydroxy groups in vicinal (a) position relative to a system of conjugated double bonds, such as an L B-unsaturated ketone grouping, or more specifically a A B-ketone grouping, by treating such steroidal compounds with an alkali metal, preferably lithium, in liquid ammonia.

There has further been discovered in accordance with the present invention a process for removing in steroidal compounds acyloxy groups in vicinal (a) position relative to a system of conjugated double bonds, such as an nip-unsaturated ketone grouping, or more specifically a A B-ketone grouping, by treating such steroidal compounds with zinc in acetic acid.

A portion of the process of the present invention as applied to steroidal A -3-ketones, may be illustrated by the following equation:

In the above equation R and R may represent a hydroxyl group in either the 0: or B configuration; or R 20 method for removing from steroidal tsp-unsaturated keto ice 2 may be hydrogen and R a hydroxyl group in either th e: or 13 configuration; or R may be hydrogen and R a hydroxyl group in either the u or 18 configuration;

In the above equation if R is hydrogen R can be any of the side chains conventionally linked to 0-17. For examplej'R maybe a keto group, a hydroxy group or esterified hydroxyrgroup. R may also represent alkyl, alkylene, oxy-alkyl, oxy-alkylene, oxo-alkyl, oxo-alkalylene, .,carboxy-alkyl, carbalkoxy-alkyl, acetyl, ,.acyloxyalkyl or. acyloxyfacetyl or the dihydroxy acetone side chain." R5,; and R togethercan also represent a spiroketal side chain such as that found in the steroidal sapogenins.

In practicing the process above outlined the steroidal A -3-ketone having a hydroxy group at 0-2 and/or 0-6 is dissolved in an organic solvent as for example tetra- ;hydrofurane and slowly added to a solution of alkalimetaLpreferably lithium, in liquid ammonia.

7 A second-portion of the present invention is illustrated by the following equation:

I Ra

acetic acid 0:

In the above equation R and R represent an acyloxy group in either the a or p configuration; or R may represent hydrogen and R an acyloxy group in either the a or ,9 configuration; or R may be hydrogen and R may represent an acyloxy group in either the at or B configuration. R and R represent the same groups as hereinbefore set-forth. It may be noted that in the above set forth reaction with zinc in acetic acid, especially good yields are obtained when the acyloxy group at 0-2 is in p configuration and while the reaction is eifective on a 0-2 a-acyloxy group the yields are rather low. On the other hand the removal of acyloxy groups at 0-6 proceeds in good yieldirrespective of the steric configuration. It may be noted further that the acyloxy groups are preferably those derived from lower fatty acids.

In practicing the process just outlined the acyloxy substituted steroid of the character set forth above is preferably dissolved in glacial acetic acid containing a small amount of water and zinc dust added thereto. The mix ture is then stirred at room temperature for a period of the order of 10 minutes to 2 hours. Purification of the resultant product gave the corresponding steroid devoid of the 0-2 or 0-6 acyloxy group.

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I 1 g. of zinc dust was mixed with 500 mg. ofthe diacetate of A -androstene-2B,17/3-diol-3-one (see the United States Patent No. 2,602,803 of Kaufmann, Rosenkranz and Berlin) dissolved in 10 cc. of acetic acid and 3 cc. of water. The mixture was stirred for 10 minutes at room temperature and filtered and the filtrate was hexane yielded 305 mg. of testosterone acetate with melting point 139-141" 0., identical to an authentic sample; Example II 1 g. of zinc dust was mixed with 500 mg. of the diacetate of A -androstene-2a,17fl-diol-3-one dissolved in hours at room temperature.

10 cc. of acetic acid and 3 cc. of water. After treating the mixture as described in Example I, there was obtained, after recrystallization from acetone-hexane, 230 mg. otunaltered starting material. The mother liquors werechromatographed in a column of activatedalumina, thus giving 15 mg. of testosterone-acetate.

Example III l g. of zinc dust was mixed with 500 mg. of 613- acetoxy-progesterone dissolved in 10 cc. of acetic acid and 13 cc. of water, and the mixture was stirred for 2 Working up the mixture in accordance with the method described in Example I aiforded 220 mg. of progesterone having a melting point of 127-1-29"C., identical to an authentic sample.

- Example IV -A solution of 1 g. of 6,3-hydroxy-testosterone (A from the group consisting of androstene and pregnene compounds having an il-unsaturated keto grouping and a hydroxy group vicinal thereto to remove the hydroxy group which comprisesreacting the steroidal compound with an alkali metal in liquid ammonia.

2. The process of claim 1 wherein the alkali metal is lithium.

3. The process of claim 1 wherein the steroidal compound having an a,p-unsaturated grouping is 'a A -3- ketone.

4. The process of claim 1 wherein the steroidal compound having an u,fl-unsaturated grouping and a hydroxy =androstene-6fl,17fl-diol-3-one) in 30 cc. of tetrahydrofurane was added dropwise to a stirred solution of 500 mg. of lithium metal in 200 cc. of liquid ammonia. The stirring was continued for 15 minutes further, 5 cc; of t-butanol was added and the stirring was continued until complete disappearance of the blue color. After evaporation to dryness, the residue was crystallized from acetone-pentane, thus giving 430 mg. of testosterone with melting point l52-153 C.

We claim:

1. A process for treating a steroidal compound selected group vicinal thereto is a 2-hydroxy-A -3-ketone.

5. The process of claim 1 wherein the steroidal compound having an a,;8-unsaturated grouping and a hydroxy group vicinal thereto is a 6-hydroxy-A -3-ketone.

6. A process for the production of testosterone which comprises reacting a G-hydroxy-testosterone with lithium in liquid ammonia.

7. A process .for the production of testosterone which comprises reacting 6fi-hydroXy-testosterone with lithium in liquid ammonia.

References Cited in the tile of this patent I V UNITED STATES PATENTS 2,787,624 Fieser Apr. 2, 1957 

1. A PROCESS FOR TREATING A STEROIDAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF ANDROSTENE AND PREGNENE COMPOUNDS HAVING AN A,B-UNSATURATED KETO GROUPING AND A HYDROXY GROUP VICINAL THERETO TO REMOVE THE HYDROXY GROUP WHICH COMPRISES REACTING THE STEROIDAL COMPOUND WITH AN ALKALI METAL IN LIQUID AMMONIA. 